LU84919A1 - MEDICAL PREPARATION CONTAINING PIRPROFEN - Google Patents

Description

CIBA-GEIGY 4-14023 / CGJ 11 / +

Basel (Switzerland) - Medical.preparation.containing Pirprofeu.

The present invention relates to a new medical preparation containing ct- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] propionic acid, hereinafter referred to as "pirprofen", as a pharmacologically active component, which contains analgesic and has anti-inflammatory activity, and which has significantly improved properties, in particular with regard to taste and stability.

Pirprofen, like its salts, is a medicinal ingredient that has excellent analgesic, anti-inflammatory and antipyretic activity. However, it has an unusually bitter taste and can cause irritation of the gastrointestinal tract. It also tends to decompose oxidatively. This can be seen from the fact that pharmaceutical preparations containing pirprofen, in free form or in salt form, easily change color when exposed to heat, light or air without protection. Furthermore, pirprofen is only moderately soluble in water as a free acid; this means that the preparation of aqueous pharmaceutical preparations containing pirprofen cannot be carried out according to conventional methods, but that unusual precautions have to be taken in order to obtain stable and compatible aqueous pharmaceutical preparations.

Surprisingly, it has now been found that pharmaceutical preparations which contain a mixture of pirprofen and a cyclodextrin and / or - an inclusion compound of pirprofen and a cyclodextrin - have a significantly higher stability are practically free of the strongly bitter taste of Pirprofens alone and to a much lesser extent cause irritation. These advantages are found in preparations which contain a mixture of pirprofen and a cyclodextrin and / or an inclusion compound of pirprofen and a cyclodextrin.

Furthermore, it has been found that pharmaceutical preparations which contain (a) a mixture of pirprofen and a cyclodextrin and / or an inclusion compound of pirprofen and a cyclodextrin and (b) an effective amount of at least one pharmaceutically acceptable basic substance are stable and practically tasteless and also cause no more irritation.

In the context of the present invention, cyclodextrins are cyclic degradation products of starch which are known per se and in which 6 to 8 glucose residues are composed in a ring; the a-cyclodextrin 6, the β-cyclodextrin preferably 7 and the y-cyclodextrin 8 glucose residues as ring members.

As an admixture to the pirprofen, the cyclodextrin is added to pharmaceutical preparations in the context of the present invention at least equimolar in relation to the active component. Preferably from 1 to 5 mol, advantageously from 1.5 to 3.5 mol, are used per 1 mol of the active ingredient. It was found that a larger excess of cyclodextrin does not bring about any further improvement in the properties of the preparations according to the invention.

The inclusion compound of pirprofen and cyclodextrin is new and forms a further subject of the present invention. It can be made by allowing pirprofen and the cyclodextrin to interact in the presence of water.

The preferred process variants for the preparation of the inclusion compound are (1) the process in saturated solution, in which water is added to a mixture of pirprofen and the cyclodextrin with stirring, preferably at a temperature between 50 and 60 ° C., and then cooled, with the inclusion connection fails; (2) the process consisting of shaking or stirring, in which pirprofen and the cyclodextrin are added to water with vigorous shaking or stirring, for example at room temperature, and the precipitated inclusion compound is obtained by filtration; (3) the kneading process, in which the cyclodextrin is vigorously stirred together with a relatively small amount of water (for example, with a water amount of about 1 1/2 times its weight), then the pirprofen is added and vigorously kneaded to obtain the To form inclusion link; and (4) the neutralization-reprecipitation process, in which first an aqueous suspension from the. Cyclodextrin and pirprofen is formed, this suspension is then converted to an alkaline solution by shifting the pH to, for example, an inorganic base such as the bicarbonate, carbonate or hydroxide of an alkali metal, e.g. of sodium or potassium, or ammonia or a solution, in particular an aqueous solution, of such a basic substance is added to the original suspension, in which the resulting solution is stirred, at which the pH of this solution is then approximately 4 to 5 is adjusted by, for example, an inorganic or organic acid such as a mineral acid, e.g. Hydrochloric or sulfuric acid, or a lower alkanoic acid, e.g. Acetic acid, is added, and finally the precipitated inclusion compound is obtained by filtration. If desired, a corresponding inclusion compound of higher purity can be obtained by removing any unreacted starting compounds, for example by washing the product with a small amount of a solvent in which pirprofen dissolves, such as ethanol, acetone or a (1: 1) mixture of ethanol and water.

Pirprofen and cyclodextrin can each be used in approximately equimolar amounts in the preparation of the inclusion compound.

However, it is advantageous to use the cyclodextrin component in excess, preferably in an amount of about 1 to about 3 moles per 1 mole of pirprofen.

As stated above, the addition of an effective amount of at least one pharmaceutically acceptable basic substance. a pharmaceutical preparation which contains a mixture of pirprofen and a cyclodextrin and / or the inclusion compound of pirprofen and a cyclodextrin which eliminates the remaining tendency of such preparations to cause irritation.

Usable inorganic basic substances are, for example, alkali metal hydroxides or alkali metal salts of inorganic or organic acids, such as, for example, phosphoric acid, phosphorous acid, carbonic acid, boric acid, acetic acid and the like, such as, for example, sodium or potassium hydroxide, lithium, sodium or potassium carbonate or - hydrogen carbonate, sodium or potassium acetate, di- or tri-trium or potassium phosphate and the like. Organic basic substances can also be used, such as piperazine, amino acids, such as lysine, and the like. It is also possible to use mixtures of basic substances, for example a mixture of an alkali metal hydroxide and an alkali metal phosphate,

The effective amount of the basic substance to be added should be so large that the system of the medical preparation according to the invention is kept at a pH of about 7 to 8. The amount also depends on the type of pharmaceutically acceptable basic substance used. The addition of an excess of the latter is undesirable because it is necessary for the preparation with regard to its. Tolerance would create problems. Both from the pharmaceutical

From the standpoint as well as from the point of view of eliminating irritation as effectively as possible, it is therefore preferable, for example, to use about 1 mol of the basic substance per 1 mol of pirprofen when sodium hydroxide is used as the base, or between approximately 0.5 and 1 mol of sodium hydroxide and between approximately Add 0.3 and 1 mol of disodium phosphate if a combination of sodium hydroxide and disodium phosphate is used as the base. Furthermore, for example, about 0.3 to 2 moles of trisodium phosphate, about 1 to 2.7 moles of disodium phosphate, or about 1 to 1.5 moles of sodium hydrogen carbonate per 1 mole of pirprofen can be used.

The pharmaceutical preparations of the present invention, which contain approximately between 50 and 500 mg of pirprofen per unit dosage form, can be used alone from a mixture of pirprofen and a cyclodextrin and / or the inclusion compound of pirprofen and a cyclodextrin, this mixture and / or inclusion compound being an effective amount can be admixed with a pharmaceutically acceptable basic substance. However, the pharmaceutical preparations according to the invention, which may be in solid or liquid form, for example in the form of powders (for example as so-called dry syrup), fine-granular granules, granules, tablets, dragees, capsules, suppositories, suspensions, syrups and the like, preferably Auxiliary and carrier materials such as fillers, binders, disintegrants, flavoring and / or coloring agents and the like. Fillers are, for example, starches, lactose, dextrin, crystalline cellulose, sucrose, glycose, hydroxypropyl starch, calcium hydrogen phosphate, calcium carbonate, magnesium metasilicate aluminate, aluminum magnesium - 6 - hydroxide, synthetic aluminum silicate and the like, while binders are, for example, starches, crystalline cellulose, agar, sodium alginate , Gelatin, arabic gum, tragacanth, guaiac gum, karaya gum, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl methyl cellulose, carboxymethyl cellulose, hydroxypropyl starch and the like can be used. Disintegrants are e.g. Starches, hydroxypropyl starches, carboxymethyl cellulose calcium, crystalline cellulose and the like, while talc, magnesium or calcium stearate, synthetic aluminum silicate and the like can be used as lubricants.

As flavorings one can e.g. Sucrose, licorice (licorice root extract), sorbitol, xylose, mannitol, hydrangea leaves, sodium glycyr rhetinate, lemon oil, vanillin, "chocolate orange" and the like, while as coloring agents all these synthetic coloring agents which are permitted for food and pharmaceuticals, e.g. Varnish dyes or iron oxides that are commonly used in medical preparations are useful. Other additives that may possibly serve the same purposes are e.g. Polyoxyethylene fatty acid esters, polyoxyethylene ethers of higher alcohols, polyoxyethylene sorbitan fatty acid esters, glycerin fatty acid esters and the like.

The preparations according to the invention are produced by methods known per se. So you can use solid preparations e.g. obtained by combining the active ingredient with auxiliary substances, optionally granulating a mixture obtained and / or pressing the mixture or granules into tablets which can be processed further into coated tablets. Suppositories are obtainable by mixing the active ingredients with a suitable suppository base, and liquid preparations by dissolving or suspending the active ingredients in suitable liquid carriers, such as water and / or ethanol.

The following examples illustrate the present invention, but are not intended to limit the scope thereof in any way.

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Example 1; 1.5 g (6 x 10 mol) of pirprofen -3 and 12.8 g (11.3 x 10 mol) of β-cyclodextrin are added to 1 liter of water, the mixture is heated to 50-60 ° C. and 0.5 Stirred for -2 hours. The temperature is slowly reduced to 20 ° C within 6-8 hours and the mixture is stored at 15-20 ° C for 1-2 days. The precipitate is filtered and dried at room temperature in vacuo, giving 8.62 g of a

Product with a decomposition product of 226-231 ° C.

The infrared absorption spectrum of this product is comparable to that of an equimolar mixture of pirprofen and ß-cyclodextrin. The . . . -1 IR spectrum shows a shift of the band at 1690 cm which corresponds to the

Carbonic acid residue of the pirprofen dimer in the equimolar mixture can be assigned to 1720 cm ^; the latter band is assigned to the carboxylic acid residue of trimers, in which the hydrogen bond is interrupted because of the inclusion of pirprofen in the β-cyclodextrin.

Furthermore, the calorimetric analysis carried out by means of differential tuning shows that the endothermic signal at 95 ° C., which occurs with an equimolar mixture of pirprofen and β-cyclodextrin. occurs, has disappeared in the product obtained. Based on these analytical results, the product obtained in the present example is identified as an inclusion compound of pirprofen and β-cyclodextrin.

-3

Example 2: 1.5 g (6 x 10 mol) of pirprofen -3 and 12.8 g (11.3 x 10 mol) of β-cyclodextrin are added to 1 liter of water, and the mixture is stirred vigorously at room temperature for one week . The precipitate is filtered off and dried at room temperature in vacuo for 8 hours, 5.27 g of a product having a decomposition melting point of 232-239 ° C. The IR spectrum and the calorimetric analysis carried out by means of differential tuning show that it is the inclusion compound from pirprofen and β-cyclodextrin, which is identical to the compound obtained in Example 1.

- 8th -

Example 3: 60 ml of water are added to 45.4 g (0.04 mol) of β-cyclodextrin, the mixture is stirred for 0.5-1 hour with a kneader and then 8.3 g (0.033 mol) of pirprofen are added. The mixture is stirred at room temperature for 10 hours, then suction filtered, and the. Wash the residue with a small amount of a mixture of water and ethanol (1: 1). The undissolved material is dried in vacuo at room temperature, giving 44 g of a product with a decomposition point of 232-237 ° C. This product is examined by means of IR spectrometry and calometric analysis (differential tuning). The results are identical to those obtained with the product of Example 1, i.e. the product is the inclusion compound of pirprofen and ß-cyclodextrin.

Example 4: To a suspension of 55 g (0.048 mol) of β-cyclodextrin and 6 g (0.024 mol) of pirprofen in 2 liters of water is added dropwise a 28 percent. given aqueous ammonia solution; the mixture is stirred until a homogeneous solution is obtained, which is stirred for a further 1 hour and then slowly brought to a pH of 4.3-4.6 with dilute hydrochloric acid. The precipitate obtained is filtered, washed with a small amount of a 1: 1 mixture of water and ethanol and dried in vacuo at room temperature, giving 22.2 g of a “product with a decomposition point of 237-239 ° C. The data of the product obtained by means of IR spectrometry and calometric analysis (differential tuning) are identical to those which were obtained for the product of Example 1. The product is identified as an inclusion compound of pirprofen and ß-cyclodextrin.

Example 5; A solution of 2.25 g (0.027 mol) of sodium hydrogen carbonate in 18-30 ml of water is mixed with 41 g (0.036 mol) of β-cyclodextrin and stirred in a mortar for 5-30 minutes. Then 5 g (0.020 mol) of powdered pirprofen are added and the mixture is stirred for 1-3 hours. A paste is formed which is dried at 40 ° C for 4-8 hours in a vacuum - 9 -; the resulting mass is pulverized and 48.5 g of a white colored powder is obtained, which consists of a mixture of ’pirprofen, ß-cyclodextrin and sodium hydrogen carbonate.

Example 6: A solution of 4.5 g (0.032 mol) of sodium hydrogen phosphate. in 25-30 ml of water is mixed with -39 g (0.034 mol) of β-cyclodextrin and stirred in a mortar for 5-30 minutes, after which 5 g (0.020 mol) of powdered pirprofen are added. The mixture is stirred for a further 1-3 hours. The resulting paste is dried in vacuo at 40 ° C. for 4-8 hours and then pulverized, giving 47 g of a product which consists of a mixture of pirprofen, β-cyclodextrin and sodium hydrogen phosphate.

Example 7: 80 mg of piperazine hexahydrate are added to 100 ml of pirprofen and 820 mg of β-cyclodextrin; the mixture is homogenized thoroughly. The addition of 10 ml of water gives a suspension of the mixture consisting of pirprofen, β-cyclodextrin and piperazine.

Example 8: A granulated powder containing 6.66% pirprofen can be made wet as follows:

Ingredients (for 1500 g)

Pirprofen 100 g ß-cyclodextrin 775 g

Sodium bicarbonate 40 g

Lactose 585 g

After thorough mixing of the individual components, a homogeneous mixture is obtained which is processed further using a dry granulate method. A granulated powder is obtained which contains 100 g of pirprofen per 1500 g of granulate.

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Example 9: Capsules containing 411 mg of the inclusion compound from pirprofen and β-cyclodextrin as described in Example 1 are produced as follows:

Ingredients .. (for 5000 capsules). Inclusion compound from pirprofen 2055 g and β-cyclodextrin (Example 1) crystalline cellulose 285 g hardened cottonseed oil 15 g

The above-mentioned components are stirred into a homogeneous mixture, of which 471 mg each are used to produce a capsule; each capsule contains an equivalent of 52 mg pirprofen.

Example 10: Tablets containing 205 mg of the inclusion compound of pir profen and cyclodextrin as described in Example 1 are produced as follows:

Ingredients (for 4000 tablets)

Inclusion compound from pirprofen 820 g and β-cyclodextrin (example 1 ’lactose 1108 g

Calcium salt of carboxymethyl cellulose 260 g hardened cottonseed oil 12 g

The tablets, each weighing 550 mg, are manufactured according to methods known per se and contain an equivalent of 24.9 mg pirprofen.

Example 11: A dry syrup containing 102 mg of pirprofen per 1 g of syrup can be produced as follows:

V

- 11 -

Components.

Pirprofen 15.00 g * β-cyclodextrin 116.25 g

Sodium bicarbonate 6.00 g

Sodium salt of carboxymethyl cellulose 1.80 g crystalline cellulose 7.95 g

The sodium bicarbonate and an equal amount of water are added to the ß-cyclodextrin, then the pirprofen. The mixture is stirred at room temperature for a few hours, an approved pigment, a suitable amount of binder and the sodium carboxymethyl cellulose being added to the mixture. The dry syrup is produced by a wet granulating process; it contains 102 mg of pirprofen in one gram of dry syrup.

Test example · 1: The inclusion ratio of pirprofen to ß-cyclo-. :: · Dextrin in the inclusion compounds of Examples 1 to 4 is determined by the "continuons change" method, which is based on the difference in absorbance in the UV range which exists between a solution of the inclusion compound and a pirprofen solution. The difference in extention in the UV range is therefore determined at a wavelength of ^ = 253 μm, the proportions of pirprofen and β-cyclodextrin being continuously changed using a 0.1 molar phosphate buffer solution (pH 7.0, 19 ° C.). The results obtained are plotted in Figure 1. They suggest that a mixture of pirprofen and ß-cyclodextrin in a molar ratio of 1: 1 has the greatest change in UV absorbance.

Illustration 1:

Plotting the extinction difference in the UV range depending on the mixing ratio of ß-cyclodextrin and pirprofen - 12 - Λ

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Mix ratio “-4 A: Pirprofen (1 x 10 M) -4 B: ß-Cyclodextrin (1 x 10 M)

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- 13 -

Test example 2:., Stability tests ..

2.1 About 3 g of pirprofen powder, further about 3 g of the inclusion compound as described in Example 1 and likewise about 3 g of the inclusion compound as described in Example 2 are placed on corresponding plates which have a diameter of 4 cm and are placed in a desiccator for one week at a constant temperature of 60 ° C and a constant humidity of 75%. The degree of discoloration of the samples is then evaluated visually.

2.2 2 g of pirprofen powder, 2 g of the inclusion compound as described in Example 1 and 2 g of the inclusion compound as described in Example 2 are enclosed in corresponding bags made of polyvinyl chloride resin and irradiated with a xenon lamp for 24 hours, after which the degree of decolorization of the samples is evaluated visually.

The results of these tests are summarized in Table 1.

Table 1: ^ ’''" ^ Conditions After 1 week After 24 hours at 60 ° C and irradiation with

Sample "Humidity of a xenon lamp of 75%

Pirprofen powder light brown brown

Inclusion connection white white from example 1

Inclusion compound white white from example 2 2.3 The stability tests described in test examples 2.1 and 2.2 are also carried out with the powder described in example 5. The results are summarized in Table 2.

y - 14 -

Table 2:.

* ^ Ss'> v * conditions. After 1 week at 60 ° C after 24 hours and exposure to humidity

Sample rate of 75% of a xenon lamp

Pirprofen powder brown yellow

Powder from Example 5 light. very faint yellow yellowish white

Test Example 3: Compatibility Test 3.1 Two samples are prepared, one by suspending about 1 g of the inclusion compound as described in Example 3 (contains 100 mg pirprofen) in 10 ml water and the other by a mixture of 100 mg pirprofen and 30 mg carboxylmethylcellulose (as a suspension stabilizer) suspended in 10 ml of water.

A tolerance test for bitterness and irritability is performed by giving 2-3 ml of each sample to 7 healthy males. The results are summarized in Table 3. The assessment given by the test subjects is expressed by the numbers 0 to 10, where 0 means an irritation which prevents the absorption of the sample, with a correspondingly reduced irritation as the number increases and 10 means no irritation at all .

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Table 3: ---- Number of people who each

Submit assessment ^^ v ^ estimate 0123 456 7 89 10

Sample Aqueous Pirprofen- 7

suspension

Inclusion compound 421 from Example 3 3.2. About 1 g of the powder described in Example 5 is suspended in 10 ml of water; 1 g of this powder contains about 100 mg of pirprofen. A tolerance test for bitterness and irritability is carried out by dispensing 2 to 3 ml of the suspension to 7 healthy males. The results are summarized in Table 4. In the same way as in test example 3.1, the assessment of the test subjects is expressed by the numbers 0 to 10.

Table 4:

Assessment 0123456789 10

Powder from Example 5 151 (number of people) 3.3 A tolerance test with both the powder and with the suspension, which is described in Example 7, is carried out analogously to the method described under 3.1 and 3.2, again 7 healthy male volunteers as Serve subjects.

- 16 -

Both the powder and the suspension are rated between 8 and 9 by all seven people, which proves that. that the irritation is largely removed.

3.4 Several samples, in which the ratio of the individual components as shown in Table 5, are prepared. Each sample is homogenized in a mortar for 3 minutes and then subjected to the tolerance test, in which 7 healthy male volunteers take part. Table 5 shows the mean of the 7 volunteers' assessments, the numbers 0 to 10 having the same meaning as in 3.1.

Table 5: V * n. Sample no. 1 2 3 4 5 6 (control) (control)

Component ^. .

(in mg)

Pirprofen 100 100 100 100 100 100

Disodium hydrogen 90 45 90 phosphate

Sodium hydrogen 45 carbonate β-cyclodextrin 815 815 775 775

Lactose 815 775

Assessment at 6-7 0-1 7-8 8-9 9-10 1-2

Compatibility test (*: Sample No. 3 is prepared by kneading the ingredients with water and then drying the kneaded mixture). The results shown above clearly show that the β-cyclodextrin used according to the present invention has the property of pirofofen to cause irritation , counteracts in a completely different way than conventional fillers.

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Test example. 4 :. Determination of the stability constant (Kc)

The pH profile of the stability constant (Kc) of the pirprofen-ß-cyclo: »dextrin inclusion complex is determined as follows:

The stability constant (Kc) within the complex to be examined

Systems Pirprofen-ß-Cyclodextrin can be calculated using equation 1) ...

according to Scott, from the difference in the UV absorption of the pirprofen in the absence or presence of a varying amount of β-cyclodextrin.

The pH profile of the stability constant (Kc) can be determined by log Kc against the pH. within a coordinate system (according to the attached sketch A). The pH profile can be used to show that the inclusion complex is most stable at a pH of 7.5.

These ascertained facts confirm the novel features of the invention that β-cyclodextrin the annoying bitterness of pirprofen in the presence of a weakly basic substance, such as e.g. Sodium hydrogen carbonate or sodium hydrogen phosphate effectively eliminated. It is also shown that the troublesome bitterness is most effectively eliminated by strong inclusion complex formation of the β-cyclodextrin at a pH of 7.5.

Credentials:.

1) Scott equation a * b 1. b - "γΐ + a = concentration of pirprofen, b = concentration of ß-cyclodextrin, d = difference in UV absorption between free and complex bound pirprofen,« - 18 - Ç. = difference in molar absorption coefficients between free c and complex bound pirprofen - Kc = stability constant of the pirprofen-ß-cyclodextrin inclusion complex 2) experimental conditions

The difference in UV absorption in the absence or presence of β-cyclodextrin is measured in a range of 253 nm (pH 5-12) and 260 nm (pH 1.6-4.5) nm.

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Claims (9)

2. A medical preparation according to claim 1, which contains the inclusion compound consisting essentially of a- [3-chloro-4- (3-pyrrolin-l-yl) phenyl] propionic acid and a cyclodextrin. 3. A medical preparation according to claims 1 or 2, characterized in that it additionally contains an effective amount of at least one pharmaceutically acceptable, inorganic or organic base. 4. A medical preparation according to claim 3, wherein said pharmaceutically acceptable inorganic base is a substance from the group of alkali metal hydroxides, phosphates, phosphites, carbonates, hydrogen carbonates, borates or acetates. 5. A medical preparation according to claim 3, wherein said. pharmaceutically acceptable organic base is a substance from the group of basic amino acids or piperazine. 6. Use of a medical preparation which is a mixture of a- [3-chloro-4- (3-pyrrolin-l-yl) phenyl] propionic acid and a cyclodextrin and / or an inclusion compound which consists of a- [3- Chlor-4- (3-pyrrolin-l-yl) phenyl] propionic acid and a cyclodextrin contains for the treatment of painful conditions, rheumatic diseases and fever. ’- 21 - 7. Use of a medical preparation which contains the inclusion compound, which essentially consists of a- [3-chloro-4- (3-pyrrolin-l-yl) - * phenyl] propionic acid and a cyclodextrin, for the hands - Pain relief, rheumatic diseases and fever. 8. Use of a medical preparation according to claim 6 or 7, which additionally contains an effective amount of a pharmaceutically acceptable inorganic or organic base, for the treatment of pain conditions, rheumatic diseases and fever. 9. Use of a medical preparation according to claim 8, which contains, as inorganic base, a substance from the group of alkali metal hydroxides, phosphates, phosphites, carbonates, bicarbonates, borates and acetates for the treatment of pain conditions , rheumatic diseases and fever. 10. Use of a medical preparation according to claim 8, which contains as organic base a substance from the group of basic amino acids or piperazine, for the treatment of pain, rheumatic diseases and fever.